Dr. Timothy Miller, MD, PhD is an excellently trained, physician scientist with a long standing interest in aging and neurodegenerative disorders. He has recently started as an Assistant Professor in Neurology at Washington University and is now seeking support for further mentorship as he focuses on a novel treatment strategy for Alzheimer's disease and Frontotemporal dementia. Building on prior experience using antisense oligonucleotides to down regulate genes in the brain and spinal cord, Dr. Miller is now using a similar strategy to either decrease overall levels of tau or decrease the 4R:3R tau ratio by changing exon splicing. He will test whether these changes in tau affect behavioral and pathological phenotype in amyloid beta depositing mice or the N279K tau mutation mice. His short term goals are to launch an academic career, expand a small translational research group, obtain independent funding (RO1), and to gain experience with understanding and treating Alzheimer's and Frontotemporal dementia mouse models. Dr. Miller's long term goal is to develop a moderate sized, exciting, research group with real impact on the understanding and treatment of neurodegenerative diseases of aging. To accomplish these goals, he has enlisted two outstanding, experienced researchers in aging research as mentors, David Holtzman and Alison Goate. His career development plan includes frequent meetings with these mentors, attendance and presentation at neurodegeneration focused seminars, attending a Neurobiology of Disease Course, attending a Designing clinical outcomes course, frequently reviewing pathology, especially tau-focused pathology, gaining experience with mouse cognitive behavioral analyses, and completing an Ethics and Research science course. Washington University School of Medicine has an outstanding track record of mentorship, in particular with K awardees and has multiple labs focused on neurodegenerative disorders. This will provide a rich and supportive scientific environment for mentorship in aging research. Dr. Miller has ample (800sq feet) laboratory space and equipment to accomplish this research project. PUBLIC HEALTH RELEVANCE: There are no treatments which substantially delay the progression of Alzheimer's disease or Frontotemporal dementia. This application tests whether changing the amount or the particular form of a protein called tau will improve behavior and pathological changes in mouse models of Alzheimer's disease and Frontotemporal dementia. This novel therapeutic strategy, if successful, would be applicable to treating human dementias.